Objective: Understanding the
pathophysiological mechanisms of migraine had led to treatment with
serotonin agonists, most notably the triptans, the first being
sumatriptan. Naratriptan is a longer acting triptan, which is well
tolerated, and has been associated with a relatively low rate of
headache recurrence. Compared with some of the other triptans, it
has a slower onset of action and lower efficacy at 2 hours. Dopamine
is also purported to play a role in the pathophysiology of migraine.
Dopamine receptor antagonists, have been shown to be highly effective
in resolving the headache as well as the nausea associated with
migraine and they have a relatively fast onset of action. Prochlorperazine,
for example, is well tolerated, and has proven efficacy in migraine,
at least when given in an intravenous route. Both oral and rectal
administration have a peak onset of action 1 hour and can be used in
a home regimen. We hypothesize that the addition of a fast peaking,
shorter-acting dopamine antagonist may improve the time to response
in persons using Naratriptan and increase the likelihood of a
complete pain-free response. Our objective in this study was to
evaluate the tolerability of, and the response to, oral Naratriptan
alone and in combination with a rectal suppository of prochlorperazine,
in migraineurs who had previously not had adequate relief with
Naratriptan.

Discussion: Naratriptan is a well-tolerated long-acting
triptan. As has recently been reported, long-acting triptans have
less efficacy at 2 hours, compared to the shorter acting drugs in
the same class. Evaluation of our primary endpoint supported this
finding, with only two persons reporting pain-free status at 2 hours.
Addition of the fast acting prochlorperazine did not improve this
endpoint, with no one reporting to be pain free at 2 hours. Given
the 6-hour half-life of Naratriptan, our finding that the pain-free
status at 4 hours was substantially higher (50%) than at the 2-hour
time point (12.5%) was expected. Our finding that Naratriptan
provided meaningful relief in over two-thirds of the migraine
attacks is similar to reports in the literature. Naratriptan as
compared to the combination regimen is superior in satisfaction with
degree of relief, and was preferred over the combination. The small
number of subjects and insufficient power for crossover analysis,
limits the ability to draw firm conclusions, but this data suggest
that the combination is neither beneficial in accelerating the onset
of action nor in increasing the overall efficacy, as compared to
naratriptan alone. The combination regimen did appear to confer
early benefit with regards to clinical disability and treatment of
nausea, but this was not sustained at the 4-hour time point. Both
regimens were very well tolerated, and specifically, there were no
reports of light-headedness, chest pains, or paresthesias. The
lackluster performance of the combination was reflected in the fact
that it was preferred in only 3 of 17 paired trials. Some subjects
stated that they would prefer an oral preparation to a rectal
suppository for ease of use, but the trial design avoided bias
by using a suppository in both regimens. Larger studies with
dopamine antagonists might be beneficial to support or refute our
findings, but pairing triptans with other classes of medication,
such as nonsteroidal anti-inflammatory drugs, may hold more promise
for added benefit.